Target product profile for readers of rapid diagnostic tests

Abstract While equipment-free visual interpretation is a benefit of lateral-flow assays, automating the reading of rapid diagnostic tests promotes proper test performance, interpretation and reporting of the results. We have created a target product profile that describes the minimal and optimal characteristics of various rapid diagnostic test readers. The product profile is intended to promote the development of effective, useful, sustainable rapid diagnostic test readers in support of health programmes worldwide. These readers may be custom hardware or software-only running on a general-purpose mobile device, for professional or lay use, and for medical or non-medical purposes. During the development of the product profile, the World Health Organization and FIND convened a development group of 40 leading scientists, experts, public health officials and regulators. We held a public consultation to which 27 individuals or organizations responded. The product profile calls for rapid diagnostic test readers that at minimum should: (i) interpret colorimetric tests with at least 95% agreement with expert visual interpretation; and (ii) automatically report results and associated data for the health programme. Optimally, readers should: (i) provide at least 98% agreement; (ii) operate with multiple models of rapid diagnostic tests; (iii) assist the user in performing each rapid diagnostic test according to the test instructions; and (iv) offer multiple configurations, operating modes and languages to suit the needs of diverse users, settings and health programmes.


Introduction
Lateral-flow rapid diagnostic tests continue to play a vital role in global health in the management and diagnosis of infectious diseases, including malaria, human immunodeficiency virus and coronavirus disease 2019 (COVID-19). Visually interpreted rapid diagnostic tests, more than any other class of diagnostics, fulfil the World Health Organization's (WHO) AS-SURED criteria (Affordable, Sensitive, Specific, User-friendly, Rapid and robust, Equipment-free and Deliverable to endusers), 1 enabling their use at the lowest levels of health care and in self-testing. 2 Their utility is, however, compromised every time a test is incorrectly performed or interpreted or its result is not available in a timely manner for clinical decision-making and surveillance. As companion tools, rapid diagnostic test readers promote more consistent, accurate test performance, interpretation and reporting, as recognized in a revision of the ASSURED criteria 3 and in comparisons of manual and automatic reports of positivity. 4 This target product profile addresses various types of rapid diagnostic test readers, with no prioritization: (i) a dedicated hardware instrument or an application that operates on a general-purpose mobile device such as a tablet or phone; (ii) a test reader designed for professional use by a health-care worker or other representative of a health programme (such as a disease control programme, a laboratory service of a health ministry or a private health-care system) or for lay use (i.e. self-and home testing); (iii) one that acts within the narrow bounds of a non-medical reader, recording the user's interpretation of the test as the definitive result and transmitting the reader's interpretation only for non-medical uses such as public health surveillance, monitoring, evaluation and external quality assessment; or one that serves as a medical reader, which provides its interpretation to its user as a basis for diagnosis and treatment as a regulated medical device or in vitro diagnostic; and (iv) a test reader offered by the manufacturer of the rapid diagnostic test or provided independently for use with one or more rapid diagnostic test brands.
Where a statement in this target product profile applies only to one type of reader, it is preceded by the name of that type, as summarized in Box 1.
Most readers in the category of device architecture are of one type or the other, but a reader may have aspects of each, for example, an application that requires a physical accessory to hold the rapid diagnostic test in front of the camera, or an instrument that relies on an application on a wirelessly connected phone. Such hybrid readers have certain application-only and other instrument-only characteristics.
While all readers must be capable of reporting results automatically to the associated health programme, the complete set of data features specified by this target product profile need not be available in the reader itself if those features are available in a digital health system with which the reader is integrated. Features for the management and analysis of the data generated by readers are not covered in this target product profile.
This target product profile is a companion to diagnostic target product profiles that state the required characteristics of a particular test. Some aspects of a reader, such as diagnostic sensitivity and specificity, can be evaluated only as a system of a particular test plus reader and should follow the requirements in the relevant diagnostic target product profile.
For each characteristic of the target product profile, an optimal criterion is to be achieved by product developers if feasible and a minimal criterion if the optimal is not feasible. In other cases, the optimal and minimal criteria are the same

Methods
This target product profile was developed according to a process based on the WHO Target product profiles, preferred product characteristics, and target regimen profiles: standard procedure, version 1.03, dated 7 December 2021.
The process was led by Francis Moussy at WHO and Wallace White and Rigveda Kadam at FIND, with advice from Sarah Charnaud at WHO.
The need for a target product profile was assessed in September 2021 and confirmed within WHO. After a review of previous target product profiles, diagnostic practices and need, an initial draft was written. The lead authors created a target product profile development group of 40 leading scientists, experts, public health officials and regulators in this field, with due attention to geographical and gender representation. All members completed the WHO declaration of interests form, with the provision that feedback from members with declared interests in this field would be analysed separately (Table 1 and Table 2).
During February and March 2022, all development group members received a draft of the target product profile and completed an online survey to elicit their scores for every minimal and optimal item in the target product profile of their rating of agreement on a Likert scale: 1, fully disagree; 2, mostly disagree; 3, neither agree nor disagree; 4, mostly agree; and 5, fully agree. As an alternative to a Likert score, members could mark "No opinion on content area. " Comments were requested on all items and were required when members marked that they did not agree (Likert score, 1-3). The levels of agreement (considered as "mostly agree" or "fully agree") were high, averaging 92% and at least 80% for every item, as shown in Fig. 1. The lead authors reviewed all comments regardless of Likert score and revised the target product profile accordingly, when practical, to address a criticism, incorporate a suggestion or avoid a clear misunderstanding of the intent.
Once the lead authors had agreed on the next draft, WHO posted it, with announcements on mailing lists and social media by WHO and FIND teams, for a public consultation over 28 days during August and September 2022. Anyone could respond by completing a typical WHO submission form, identifying themselves and listing their comments and suggested amendments.
A total of 27 individuals or organizations submitted 137 requests for changes. In the same way as for the survey of the development group, the lead authors reviewed all comments and revised the target product profile when appropriate and feasible. The proposed revisions to the performance section were reviewed by the development group members without conflicts of interest (Table 1).
WHO then released the current version of the target product profile. 5

Profile
Below information is available in a tabular format in the published target product profile. 5

Intended use
Minimal Non-medical: To collect user interpretations and other data from rapid diagnostic tests. Medical: To interpret rapid diagnostic tests to aid clinical decisions and to collect other data from rapid diagnostic tests.

Optimal
Same as minimal, plus: To support proper test performance.

Minimal and optimal
The reader may be used in screening, diagnosis or management of disease. The reader transmits test data, patient data entered by the user and contextual data to the health programme.

Notes
A non-medical reader does not show its interpretation to the user. For medical readers, in most countries each combination of reader and test is subject to medical regulation.

Minimal and optimal
All levels of health care as well as nonhealth-care settings. 6

Notes
Examples of non-health-care settings: homes, schools, workplaces, transport hubs, high-traffic areas.

Minimal and optimal
Professional use: Health-care worker, including community health worker, with at least basic literacy and minimal training or any health-care worker with additional training. Lay use: Person with at least basic literacy but no formal education in a relevant field of health care or medical discipline. Application: Person with access to a mobile device and basic application skills. The operator may have requirements for access that must be met by the reader.

Notes
Examples of lay users: self-testers, caretakers, workplace screeners, school screeners. Accessibility: To design a reader appropriately, see Web content accessibility guidelines 7 and characteristic 28 (that is, patient or case data collected).

Minimal
Instrument and application: Operate with one test at a time.

Optimal
Instrument: Offered in two or more configurations: single-bay, operates with one test at a time; and multi-bay, operates with multiple tests in parallel, with random access and capability of testing different analytes simultaneously. Application: Interprets one test at a time, and can guide administration of multiple tests in parallel, tracking the timing of each.

Device architecture
Instrument: dedicated hardware, as most readers have been. Application: software that operates on general-purpose mobile devices.

User
Professional use: by a health-care worker. Lay use: self-testing and similar use by the general public.

Intended use
Medical: shows its interpretation of the rapid diagnostic test to the user. Non-medical: does not show its interpretation to the user. Both send data to the health programme.

Optical technology
Colorimetric: detection from changed presence, intensity or colour of a line illuminated by visible light; includes tests that can be read visually, with no instrument. Fluorescent: detectable, typically in otherwise darkness, by emission of a line near one wavelength when excited near another wavelength. Luminescent: similar to fluorescent but without excitation.
Rapid diagnostic test readers Wallace White et al.

Notes
See characteristics 20 (that is, help provided by the reader in timing of rapid diagnostic test interpretation) and 21 (that is, help provided by the reader on other aspects of rapid diagnostic test instructions) on timing of interpretation. Parallel, random-access testing: In "walk away" mode, while one test develops in the reader, a user can start additional tests for more analytes for the same patient or for other patients. A multibay instrument may therefore provide throughput of multiple single-bay instruments at lower cost, space or administration, although with less flexibility and more complexity for the user

Minimal and optimal
Small, portable table-top device.

Notes
Appropriate size may depend on the features of the instrument. The instrument should be designed to be moved easily and to withstand drops and impacts associated with portable (not necessarily hand-held) devices (see characteristic 28, that is, patient or case data collected).

Additional physical components required for use (application only)
Minimal Acceptable if they are readily portable and nearly universal (not specific to a few models of mobile devices or rapid diagnostic tests).

Notes
Acceptable example for minimal: an optical calibration card. Dependence on such components is not optimal because of costs, logistics and (if not single-use) maintenance.

Optimal
Same as minimal, plus: User-replaceable rechargeable battery sufficient for an 8-hour shift or user-replaceable singleuse batteries.

Notes
The reader's documentation should explain the electrical interfaces, including power consumption, cord length, mains plug style and single-use battery model, so that implementers can plan accordingly.

Minimal
Any setting in which the user can see well enough to run the test. Infrequently, the reader may signal that it cannot operate in the current lighting and should indicate how the lighting should be changed to enable operation.

Optimal
Any setting in which the user can see well enough to run the test.

Notes
Examples: indoors without artificial lighting; indoors with no windows and fluorescent lighting; mixed lighting;

General operating environment (instrument only)
Minimal 10-40 °C and ≤ 90% non-condensing humidity at an altitude ≤ 2500 m; can withstand dusty conditions and water splashes.
Optimal 5-45 °C and ≤ 98% non-condensing humidity at an altitude ≤ 4000 m; can withstand dusty conditions and water splashes.

Biosafety (instrument only)
Minimal and optimal Easy decontamination of surfaces with 70% isopropyl alcohol, 70% ethyl alcohol or a bleach solution with 0.5% chlorine.

Minimal and optimal
Application: Software updated automatically or manually depending on health programme preference and within the limits of the update policy of each mobile device, as necessary to ensure compatibility with the latest operating system.

Minimal
The application maker shall publish and maintain a list of Android mobile devices and operating system versions, including low-priced devices and older versions, that have been determined to be compatible with the application. Devices that use the application shall remain functional for other applications and uses.

Optimal
Same as minimal, plus: Most Android (lay use: and iOS and iPadOS) mobile devices with a rear-facing camera that are readily available in low-and middle-income countries. The application maker may provide an optical performance check to allow users to enable operation on any device that passes the check.

Notes
At present, the capability of the camera of a mobile device for rapid diagnostic test analysis, particularly as a medical reader, is difficult if not impossible to determine from its advertised specifications. The minimal may be adequate for health programmes that provide mobile devices to their health-care workers. The optimal is intended for use in scenarios with less control, including bring-yourown device.

Minimal
The reader's manufacturer shall publish and maintain a list of compatible rapid diagnostic test models. The reader shall be compatible with rapid diagnostic tests that have user markings on them.

Optimal
Same as minimal, plus: The reader shall be compatible with rapid diagnostic tests that were not necessarily designed for use with a reader, e.g. rapid diagnostic tests with no computer-visionfriendly markings; strips without a plastic cassette (dipsticks). The reader shall be compatible with multiple brands and types of rapid diagnostic tests. The reader shall use one-dimensional and two-dimensional barcodes, if present on the rapid diagnostic tests, to identify the model, lot, expiration or serial number.

Notes
User markings: It is common for users to write the name of the patient or another identifier on the rapid diagnostic test. No medical reader is expected to be universal in the sense of reading all rapid diagnostic test models, as the reader's performance must be validated with each rapid diagnostic test model. Barcoded serial numbers can enable tracing of each test, verification of authenticity and prevention of reuse, but they may remain rare in low-and middle-income countries, partly because of the cost. In view of lack of standardization of their content, the design of barcodes should be integrated between reader and rapid diagnostic test, which is beyond the scope of this document.

Compatible rapid diagnostic test types by result type
Minimal Qualitative.

Optimal
Qualitative; semiquantitative threshold, by comparison of intensity of a test line to a reference; semiquantitative levels, such as low, medium or high; and quantitative.

Notes
The design of semiquantitative and quantitative tests may require integra-

Compatible rapid diagnostic test types by optical technology
Minimal Instrument: Colorimetric (visible), fluorescent or luminescent lateral flow assays.

Notes
The design of fluorescent and luminescent tests may require integration between the reader and rapid diagnostic test, which is beyond the scope of this document.

Compatible rapid diagnostic test types by number of lines, including test and control
Minimal 2 or 3 lines.

Notes
Example of a three-line test: a malaria test with a control line and lines for Plasmodium falciparum and P. vivax.

Minimal
For each country in which the reader is deployed, one popular language, such as the official language or de facto national language, and any language mandated by local regulatory or trade compliance requirements.

Optimal
Same as minimal, plus: Additional languages to enable use by other residents of that country.

Minimal
The reader provides a readnow mode, in which the user presents the test to the reader and the reader promptly interprets the test.

Optimal
The reader provides a read now mode (see minimal) and a walk away mode, in which the user presents the test to the reader at the start of the development period, and the reader controls when the test is interpreted.

Notes
In a walk away mode, the reader may be able to release a positive result before the development period has elapsed, if the rapid diagnostic test manufacturer provides for this.

Minimal
None.

Optimal
In a read now mode, the reader shall provide a countdown timer to prompt the user when the rapid diagnostic test is ready to be read and before expiration of the reading period. The reader shall set the times according to each rapid diagnostic test's quick reference instructions or job aid. The possibility of overriding the elapsed time limits shall be configurable by the health programme. Application: During the countdown, the user shall be able to use the mobile device for other tasks and still receive a prompt from the application when the rapid diagnostic test is ready to be read.

Notes
Regarding elapsed time data, see characteristics 23 (that is, help provided by the reader after determination of the result; lay use only) and 29 (that is, contextual data collected).

Help provided by the reader on other aspects of rapid diagnostic test instructions
Minimal None.

Optimal
The reader shall provide the user with access to rapid diagnostic test instructions equivalent to the quick reference instructions or job aid. The reader may provide enhanced instructions, such as videos, audio and photographic examples of results.

Notes
Minimal: Users should follow regular instructions for use of the rapid diagnostic test, as they would without the reader. Optimal: If the reader provides enhanced instructions, their role in regulatory authorization of the test should be considered, as should their usability for both new and frequent users (see characteristic 12, that is service and maintenance). Regardless of this characteristic, the reader will include instructions for use, such as how to place the rapid diagnostic test and properly illuminate it.

Minimal
The reader displays basic result terms such as positive, negative and invalid.

Optimal
The reader displays extended result messages from the quick reference instructions of each test. Each health programme can provide messages for each type of result of each test, with referral and other resources.

Notes
Other examples of basic result terms, depending on the test, are reactive, nonreactive and invalid. Extended result messages often explain the meaning and potential limitations of a result.

Rapid diagnostic tests other than qualitative colorimetric: performance
Minimal and optimal Equivalent to state-of-the-art readers.

Compliance with medical standards for design and manufacture (medical only)
Minimal ISO 13 485:2016 Medical devices -Quality management systems -Requirements for regulatory purposes. IEC 61 010-2-101:2018 Safety requirements for electrical equipment for measurement, control and laboratory use -Part 2-101: Particular requirements for in vitro diagnostic medical equipment. Applicable standards associated with the above.

Minimal
Brand and type of test as entered by the user. Underlying values and outcome of quality controls (see characteristic 23, that is, help provided by the reader after determination of the result; lay use only). Non-medical: Result as entered by the user. Result as calculated by the reader. Intermediate data used to calculate the result (e.g. intensities of test and control lines).

Optimal
Replace first item in minimal with: brand and type of test, by photographing the test or its packaging. Same as rest of minimal, plus: Lot number and expiration date of the test (possibly by photographing the test and its packaging); rapid diagnostic test instruction version; rapid diagnostic test photograph(s) used to calculate the result; specimen type (e.g. whole blood, serum) and volume; and other relevant diagnostic data entered by the user.

Notes
Each health programme should be able to choose whether to require their users to enter lot and expiration data. Because of limited connectivity and storage in many settings, the reader should provide appropriate options for image resolution and cropping. Multiple images may be appropriate: one cropped to the region of the control and test lines for evidence of the result, and another of the entire rapid diagnostic test for supervision of the type of test. Health programmes may prefer to transmit images only in certain cases, such as faint lines and invalid results or during certain research programmes. As noted in characteristic 16, images of the entire rapid diagnostic test may include patient-identifiable information.

Minimal and optimal
As determined by the health programme and in compliance with local regulations (e.g. patient identification, location, consent, symptoms).

Notes
Data needs should be balanced with the burden of data entry on users. As noted in the preface, data features can be provided by integrating the reader with a digital health system with those capabilities.

Contextual data collected
Minimal User identification (lay use: if required by the health programme). Location of testing as text entered manually, such as an address or facility name (if enabled by the health programme). Time and date of test. Manufacturer and model name of reader. Instrument: Serial number of reader. Reader software or firmware version. Application: Model of mobile device. Operating system version.

Optimal
Same as minimal plus: Automatic geolocation of test (e.g. via global positioning system, if enabled by the health programme); reader operational data for administration, maintenance and performance metrics (e.g. self-checks, calibration, quality control samples); others as determined by the health programme.

Notes
Almost all these data can and should be collected automatically rather than entered manually.

Optimal
Typing. Scanning one-dimensional and two-dimensional barcodes.

Notes
The user can choose one of these methods for entering the types of data listed above. When possible, the reader should instead collect data automatically or enable the user to select from lists, to avoid dataentry errors.

Notes
Reader memory is intended as a log of recent results and a temporary repository of results awaiting transmission to a server with the data connectivity features described later. At least certain images should be kept with recent results. See characteristic 29 (that is, contextual data collected) for considerations of image types. Application: This assumes the mobile device has enough space.

Role-based access control (professional use only)
Minimal and optimal Provides access to specific data and reader features for users with different roles.

Notes
Roles may include data managers at several levels (e.g. supervisor, site administrator, national manager) and rapid diagnostic test user (health-care worker).

Minimal
Instrument: mobile network, Wi-Fi, USB or Bluetooth.

Optimal
Instrument: mobile network and at least one of Wi-Fi, USB, Bluetooth or Ethernet.

Minimal and optimal
Application: mobile network or Wi-Fi as provided by the mobile device.

Notes
Throughout this section, as noted in the preface, data features can be provided by integrating the reader with a digital health system with those capabilities.

Policy & practice
Rapid diagnostic test readers Wallace White et al.

Minimal
The user shall be able to perform tests (medical: and receive results) offline, in which case the reader shall transmit those data when back online.

Optimal
Same as minimal, plus: The reader shall transmit automatically (without user action) in the background when back online, prioritizing basic data elements before sending larger, secondary elements such as images.

Minimal
The reader supports FHIR® or JSON.

Optimal
The reader supports FHIR® and JSON.

Notes
For connections to systems such as laboratory information systems, electronic health records, national registries and surveillance systems.

Minimal and optimal
The health programme shall be able to choose the destination(s) of the reader's data.

Notes
The reader's manufacturer and other groups should require permission from the health programme to receive any data.

Minimal and optimal
The health programme shall be able to manage the reader in compliance with local regulations on data ownership.

Security and privacy
Minimal and optimal To facilitate use by health programmes in accordance with the laws, regulations and policies in their settings and with best practices, the reader shall provide configurable features so that personal data can be: (a) gathered transparently to users and patients, including consent; (b) collected and processed only for purposes compatible with the health programme's purposes; (c) limited to what is relevant and necessary; (d) collected accurately; (e) stored in identifiable form no longer than necessary; and (f) secured for integrity and confidentiality, with encryption at rest and in transmission.

Notes
(a)-(f) are adapted from the European Union General Data Protection Regulation (GDPR) 2016/679 (GDPR), article 5, sec. 1. Note that not all the GDPR is relevant or appropriate to this reader in these settings.

Minimal and optimal
Pricing should be as low as sustainably possible while maintaining quality, based on evidence of the cost of goods sold plus a reasonable profit margin, ensuring security of supply and a fair return on investment for suppliers. Pricing should be affordable, transparently published and inclusive of all fees, including any for warranties, support and software updates.

Conclusion
With input from invited experts and the public, we have developed a target product profile for automatic readers of rapid diagnostic tests to address a range of possible uses.

Policy & practice
Rapid diagnostic test readers Wallace White et al.